Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou, China.
Department of Pathology, Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
Mol Cancer. 2021 Jan 4;20(1):6. doi: 10.1186/s12943-020-01299-y.
De novo and acquired resistance, which are mainly mediated by genetic alterations, are barriers to effective routine chemotherapy. However, the mechanisms underlying gastric cancer (GC) resistance to chemotherapy are still unclear. We showed that the long noncoding RNA CRNDE was related to the chemosensitivity of GC in clinical samples and a PDX model. CRNDE was decreased and inhibited autophagy flux in chemoresistant GC cells. CRNDE directly bound to splicing protein SRSF6 to reduce its protein stability and thus regulate alternative splicing (AS) events. We determined that SRSF6 regulated the PICALM exon 14 skip splice variant and triggered a significant S-to-L isoform switch, which contributed to the expression of the long isoform of PICALM (encoding PICALML). Collectively, our findings reveal the key role of CRNDE in autophagy regulation, highlighting the significance of CRNDE as a potential prognostic marker and therapeutic target against chemoresistance in GC.
新生和获得性耐药主要由遗传改变介导，是有效常规化疗的障碍。然而，胃癌（GC）对化疗耐药的机制尚不清楚。我们表明，长链非编码 RNA CRNDE 与临床样本和 PDX 模型中的 GC 化疗敏感性有关。CRNDE 在耐药 GC 细胞中减少并抑制自噬流。CRNDE 直接与剪接蛋白 SRSF6 结合，降低其蛋白质稳定性，从而调节选择性剪接（AS）事件。我们确定 SRSF6 调节 PICALM 外显子 14 跳过剪接变体，并引发显着的 S 到 L 同工型转换，这有助于 PICALM 的长同工型（编码 PICALML）的表达。总之，我们的研究结果揭示了 CRNDE 在自噬调节中的关键作用，强调了 CRNDE 作为 GC 化疗耐药的潜在预后标志物和治疗靶标的重要性。
